Progress in understanding the mechanism of cell division has come slowly. Scientists have studied cell division for more than 100 years and about 30 years ago discovered the "contractile ring," which squeezes one cell into two daughter cells. The ring acts like a microscopic chain link belt tightening around the middle of a cellular balloon, until two cells form. But little is known about how the ring components or links assemble and generate force.

New research is revealing hints about how the ring is made. Such knowledge about the details of cell division may help other researchers better understand human development and diseases such as cancer. Researchers have known for some time the ring contains proteins called actin and myosin. In the ring, actin protein is present in long chains, or polymers, which take the form of long filaments, "the chain link belt." Myosin has been thought to help shrink the ring by moving actin filaments together. Most researchers believed that actin filaments in the ring are fairly stable and that myosin slowly pulls these filaments together to squeeze the cell into two.

Now, Columbia University Health Sciences researchers have found that the ring is a much busier place, where actin filaments are constantly being made and then disassembled. The researchers also have found that other proteins in the ring, called Arp2/3 complex, formin, and profilin, are responsible for building actin filaments in the ring. They showed that this constant building of actin filaments works in the initial formation as well as the shrinkage of the ring.

Dr. Fred Chang, assistant professor of microbiology at P&S, and Robert J. Pelham, a doctoral student in the Integrated Program in Cellular, Molecular, and Biophysical Studies, reported their research about the dynamic nature of the contractile ring in the Sept. 5 Nature. "The work challenges some old dogmas in cell division and is making researchers think differently about how the process actually works," Dr. Chang says.

Dr. Chang and Mr. Pelham work with the model organism Schizosaccharomyces pombe, a fission yeast that divides much like animal cells and employs proteins similar to those used in human cell division. One advantage of working with these yeast cells is that researchers can easily identify and analyze mutant cells defective in cell division.

In one set of experiments, the researchers observed the dynamics of the ring by attaching green fluorescent tags to ring proteins. Under the microscope, these yeast cells have a fluorescent ring when they are dividing. To follow how tagged proteins incorporate themselves into the ring, the researchers "photo bleached" the fluorescent ring with laser light, wiping out the fluorescence. The ring began to glow again in a minute, indicating new proteins from elsewhere in the cell were rapidly joining the ring. As the ring does not get larger, the findings implied that proteins come off the ring rapidly, too.

In another experiment, when actin filament addition was inhibited in a mutant or by a drug, the ring rapidly disappeared. Although there were hints to the ring's dynamic nature previously, Dr. Chang and Mr. Pelham were surprised to see how quickly the ring constantly rebuilds itself even as it slowly shrinks.

In contrast to previous dogma that suggests myosin pulls slowly on stable actin filaments during cleavage, the Columbia studies suggest a new view in which actin and myosin do not have a long-term relationship, but meet only transiently. The rapid exchange of subunits actually may regulate the rate of cleavage. In mutants in which actin filaments are made at a slower pace, the ring actually shrinks more slowly. The investigators speculate that ring dynamics may regulate the interaction between actin and myosin, or that the act of filament assembly may even contribute directly to force generation.

The investigators also identified other proteins at the ring that are needed to make the new actin filaments. Formin and profilin were known to be required for ring formation, but their precise function was not clear. Arp2/3 was a known actin filament maker, but its role in cell division was not known. Using mutant yeast lacking the proteins, the researchers found that each protein is important for forming new actin filaments at the ring. How these proteins work together to make actin filaments and how other proteins may work to take actin filaments apart are now important topics of research.

Dr. Chang and Mr. Pelham also are investigating whether contractile rings have similar properties in other organisms, such as humans and sea urchins. Although their findings are not directly applicable to oncology today, the research someday may help cancer researchers understand how cell division goes awry in cancerous cells. "It is important to learn how cell division occurs, because there is growing evidence that a slip-up in cell division can contribute to the development of cancer," Dr. Chang says.

The National Institutes of Health's National Institute of General Medical Sciences and the American Cancer Society supported this research.